Genetic control of heart development

Group leader : R. Kelly

Our group addresses how different progenitor populations contribute in an integrated manner to the definitive heart and how these processes are regulated by genes and intercellular signalling pathways.

FOR BEGINNERS

The heart is the first organ to function in the embryo and cardiac development involves complex interactions between multiples genes, progenitor cell populations and signalling events. This complexity is reflected in the fact that defects in heart development result in congenital anomalies affecting 1% of live births.

Our group studies the genetic control of heart development, focusing on two critical processes:

Firstly, we are investigating the progressive formation of the embryonic heart by addition of myocardium to the poles of the heart tube, from progenitor cells in pharyngeal mesoderm termed the second heart field. This recently discovered population of progenitor cells gives rise to a large part of the definitive heart including the right ventricle, outflow tract and part of the atria.

Cartoon showing addition of second heart field progenitor cells (blue) to the arterial and venous poles of the heart tube between embryonic days (E) 7.5 and 10.5 of mouse development.

The outflow tract is a major hotspot for common forms of congenital heart defects. We are investigating the properties of second heart field cells and the regulatory mechanisms that control their addition to the heart tube, including the role of the DiGeorge syndrome gene Tbx1. The genetic program of the second heart field is shared with pharyngeal mesodermal cells giving rise to skeletal muscles of the head and we are also addressing how a single progenitor cell population gives rise to divergent cardiac and skeletal muscle fates.

Secondly, we are studying the establishment of the cardiac conduction system. This constitutes the electrical wiring of the heart and coordinates the heartbeat. Using a variety of genetic approaches in mice we are investigating the origins and establishment of these specialized myocytes, during normal development and in pathological situations.

Studying heart development in the mouse provides both basic insights into the mechanisms underlying organogenesis and biomedically relevant findings. These include insights into the etiology of congenital heart defects and conduction anomalies, as well as into the properties of cardiac progenitors cells relevant for the repair and regeneration of damaged hearts.

FOR SPECIALISTS

Our group addresses how different progenitor populations contribute in an integrated manner to the definitive heart and how these processes are regulated by genes and intercellular signalling pathways.

1. Second heart field cardiac progenitor cells

Connexin40-GFP expression in coronary endothelial cells showing abnormal patterning of the coronary arteries in the ventral region of the heart.

The second heart field is a recently identified population of cardiac progenitor cells located in pharyngeal mesoderm that gives rise to atrial myocardium, the right ventricle and the outflow tract of the heart, a region affected in 30% of congenital heart defects. We are investigating the genetic regulation, epithelial nature and dynamic behaviour of second heart field progenitor cells in the early mouse embryo. Different regions of the heart are pre-patterned within the second heart field and we are studying how the transcription factor TBX1 controls development of a subpopulation of progenitor cells that give rise to myocardium at the outlet of the right ventricle. TBX1 is the major candidate gene for DiGeorge syndrome (1 in 4000 live births), a common cause of outflow tract malformation in man. We are also studying how defects in early steps of heart morphogenesis impact on later stages of development including outflow tract septation, coronary arteriogenesis and ventricular growth.

Pharyngeal mesoderm is the source not only of cardiac muscle but also of a subset of craniofacial skeletal muscles, known as branchiomeric muscles. These muscles are specified in the core of the pharyngeal arches at midgestation and regulate jaw opening and closure, facial expression and pharyngeal and laryngeal function. They differ fundamentally from somite derived muscles that constitute the body and limb musculature. Branchiomeric skeletal muscle progenitor cells are dependant on Tbx1 and develop from a common pharyngeal mesodermal progenitor population with second heart field derived parts of the heart. We are investigating how divergent myogenic fates arise within pharyngeal mesoderm and the role of Tbx1 in this cardiocraniofacial developmental field.

The ventricular conduction system coordinates the heartbeat and ensures rapid transmission of the electrical signal to the apex of the heart to initiate ventricular contraction. We are using clonal analysis and genetic tracing to study the development of these specialised cardiomyocytes. We are also generating and characterizing mouse models with defective conduction system morphology and function. The development of trabeculae, transient sponge-like myocardial projections in the fetal heart, is also under analysis. Persistence of trabeculae results in ventricular non-compaction, associated with conduction anomalies, in human patients.

Selected publications

PUBLICATION

March 30th, 2017

Epithelial tension in the second heart field promotes mouse heart tube elongation.

Camille Dumas

Estelle Jullian

Lucile Miquerol

Researcher

Lucile’s research projects concern the development of the ventricular conduction system to address the question: how does the heart beat in rhythm? We employ genetic tools to perform lineage analysis of the ventricular conduction system and to study the development of the conduction system in embryos with congenital heart diseases. The use of the Cre-Lox system in combination with conditional reporter mice allows us to visualize and trace the conduction system and its progenitors to understand when these cells diverge from the myocardium and what is happening during pathological conditions.

Charlotte Thellier

Magali Theveniau Ruissy

Researcher

Magali’s research interests focus on cellular and molecular processes taking place in the Second Heart Field. One of the major attractions of this subject is that a complex arterial pole which connects the aorta and pulmonary trunk, integrating migrating neural crest cells to make valves and connecting to the coronary artery tree, takes its origin from a simple progenitor cell population. In addition I am looking at early development and patterning of the proximal coronary arteries.